Widespread remodeling of the m6A RNA-modification landscape by a viral regulator of RNA processing and export

Kalanghad Puthankalam Srinivas, Daniel P. Depledge, Jonathan S. Abebe, Stephen A. Rice, Ian Mohr, Angus C. Wilson

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

N6-methyladenosine (m6A) is the most abundant internal messenger RNA (mRNA) modification, contributing to the processing, stability, and function of methylated RNAs. Methylation occurs in the nucleus during pre-mRNA synthesis and requires a core methyltransferase complex consisting of METTL3, METTL14, and WTAP. During herpes simplex virus (HSV-1) infection, cellular gene expression is profoundly suppressed, allowing the virus to monopolize the host transcription and translation apparatus and antagonize antiviral responses. The extent to which HSV-1 uses or manipulates the m6A pathway is not known. Here, we show that, in primary fibroblasts, HSV-1 orchestrates a striking redistribution of the nuclear m6A machinery that progresses through the infection cycle. METTL3 and METTL14 are dispersed into the cytoplasm, whereas WTAP remains nuclear. Other regulatory subunits of the methyltransferase complex, along with the nuclear m6A-modified RNA binding protein YTHDC1 and nuclear demethylase ALKBH5, are similarly redistributed. These changes require ICP27, a viral regulator of host mRNA processing that mediates the nucleocytoplasmic export of viral late mRNAs. Viral gene expression is initially reduced by small interfering RNA (siRNA)-mediated inactivation of the m6A methyltransferase but becomes less impacted as the infection advances. Redistribution of the nuclear m6A machinery is accompanied by a wide-scale reduction in the installation of m6A and other RNA modifications on both host and viral mRNAs. These results reveal a far-reaching mechanism by which HSV-1 subverts host gene expression to favor viral replication.

Original languageEnglish (US)
Article numbere2104805118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number30
DOIs
StatePublished - Jul 27 2021

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We are grateful to members of the I.M./A.C.W. laboratory for their input during the course of these studies and to Yan Deng from the New York University Langone Microscopy Laboratory (RRID: SCR_017934), a core facility partially supported by Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center. J.S.A. was supported by the Vilcek Institute of Graduate Biomedical Sciences. This work was supported by NIH Grants AI073898 and GM056927 (I.M.), AI152543-01 (I.M. and D.P.D.), AI130618 and AI147163 (A.C.W.), and AI151617 (S.A.R.).

Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.

Keywords

  • Direct RNA sequencing
  • Herpes simplex virus
  • N-methyladenosine
  • Nanopore
  • RNA modification

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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